The present U.S. epidemic of opiate abuse and addiction continues to worsen rapidly and shows no signs of abating. As a result, narcotic overdose deaths are increasing and now exceed the number of deaths annually from motor vehicle accidents and from firearm-related incidents nationwide. Heroin-related overdose deaths have more than quadrupled since 2010. Although the increasing availability of nasal Narcan, (antidote for narcotic overdose) has saved many lives, the tightening of controls on prescription narcotics has driven many dependent users to the much cheaper (per dose) heroin and heroin-fentanyl mixtures. The appearance of designer fentanyl-related narcotics produced by Asian criminal groups attempting to circumvent controlled substance laws has become another dimension of the problem and a major concern of the Drug Enforcement Administration. We are pursuing several approaches in order to further understand the complex pharmacology of opioid drugs and develop strategies for treatment and prevention of their abuse and side effects. One of these strategies of the is the development of a dual anti-heroin anti-HIV vaccine. A successful vaccine of this type would suppress heroin abuse and protect against HIV infection from any route of exposure. Injection drug use is a major factor in the transmission of HIV-1. Suppression of the accompanying needle sharing would limit the spread of HIV and hepatitis in injection drug users. Such a vaccine should also be a valuable adjunct to prevent relapse in newly abstinent former narcotic abusers. This is an important consideration as the relapse rate for those able to quit is as high as 60% in the first year. We are continuing to prepare and evaluate experimental vaccines based on the novel approach of utilization of metabolically stable heroin-mimetic haptens. These haptens were then covalently attached to the highly immunogenic tetanus toxoid (TT) with or without and HIV component and formulated with the Army Liposome Formulation. One such vaccine was derived from the heroin hapten 6-Amhap. The HIV portion of the vaccine utilized a cyclic V2 (cV2) peptide previously identified as a correlate of prevention of acquisition of HIV in the RV144 phase III clinical trial. RV144 is the only HIV vaccine trial that has demonstrated efficacy to date. We immunized mice and sera were assessed for antibody titer to heroin and cV2, and affinity to heroin, its metabolites and other opioids. We assessed efficacy against heroin by subcutaneous heroin challenge. The TT-6-AmHap vaccine significantly reduced heroin-induced antinociception and locomotion behavioral changes. Competition ELISA demonstrated that 6-AmHap-induced antibodies bound heroin and its metabolites, 6-acetylmorphine, morphine, and other abused opioids, including oxycodone, hydrocodone and hydromorphone. The antibodies did not cross-react with the therapies for substance abuse or the overdose rescue drug naloxone. Antibody titers to cV2 were in the millions and bound to gp120 and gp70V1V2. The heroin-HIV vaccine induced protection against heroin challenge and very high titer cV2 antibodies, a proposed a correlate of efficacy in RV144. We conclude that an effective heroin-HIV vaccine is feasible based on our data.